Comparison of conditioning impairments in children with Down syndrome, autistic spectrum disorders and mental age-matched controls

Reed, Phil; Staytom, L.; Stott, Sarah; Truzoli, R.

doi:10.1111/j.1365-2788.2011.01454.x

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…However, neural activity was only significantly correlated to behavioral performance during reversal. Our data also show that a neurodevelopmental example of an interneuron deficit leads to difficulty navigating a reversal task (15,17,26) in agreement with reports from human patients with schizophrenia and impaired cognition (45–48). In the Plaur mice, these behavioral deficits likely reflect decreased numbers of fast-spiking PV + interneurons, which led to altered encoding of decisions (correct vs error), elevated baseline OFC activity, diminished differences between baseline firing and trial epochs, a reduction in predicted outcome encoding, and a lack of correlation between OFC firing and behavior.…”

Section: Discussionsupporting

confidence: 91%

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Bissonette

Schoenbaum

Roesch

et al. 2015

Biological Psychiatry

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Background Cerebral cortical GABAergic interneuron dysfunction is hypothesized to lead to cognitive deficits co-morbid with human neuropsychiatric disorders, including schizophrenia, autism and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia. Methods We examined the role of parvalbumin interneurons in orbitofrontal cortex (OFC) during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analysed during correct and incorrect decision choices and reward receipt. Results Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behaviour, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across tasks phases during the decision period. Conclusions These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in OFC. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompanies the loss of these GABAergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia.

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Section: Discussionsupporting

confidence: 91%

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Bissonette

Schoenbaum

Roesch

et al. 2015

Biological Psychiatry

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“…Despite aspects of learning theory being used to a degree in educational strategies in autistic children, there has been surprisingly little clinical investigation on the nature of reward-based learning in ASD. One study reported that ASD patients performed as well as their mental age-matched controls in an instrumental conditioning task (Reed, Staytom, Stott, & Truzoli, 2011), suggesting a discrepancy with the data obtained from the NRXN1␣ KO animal model. However, studies that directly assess instrumental learning in patients are rare and this topic certainly requires further exploration, both clinically and preclinically, before conclusions on the translational validity of this aspect of the model can be determined.…”

Section: Discussionmentioning

confidence: 97%

Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Esclassan¹,

François²,

Phillips³

et al. 2015

Behavioral Neuroscience

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Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.

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“…Certain aspects of learning are identified as strengths. Children with DS perform favorably in paradigms of observational learning (observing the actions of others) [Reed et al, ] and when associating objects with rewards [Kogan et al, ]; whereas, they have greater difficulty with instrumental learning (manipulating the environment to meet their needs) [Wishart, ; Ohr and Fagen, ; Reed et al, ]. Their higher social motivation and responsiveness to positive reinforcement likely make socially oriented learning more successful.…”

Section: Cognitive Functioningmentioning

confidence: 99%

Down syndrome: Cognitive and behavioral functioning across the lifespan

Grieco¹,

Pulsifer²,

Seligsohn³

et al. 2015

American J of Med Genetics Pt C

337

246

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Individuals with Down syndrome (DS) commonly possess unique neurocognitive and neurobehavioral profiles that emerge within specific developmental periods. These profiles are distinct relative to others with similar intellectual disability (ID) and reflect underlying neuroanatomic findings, providing support for a distinctive phenotypic profile. This review updates what is known about the cognitive and behavioral phenotypes associated with DS across the lifespan. In early childhood, mild deviations from neurotypically developing trajectories emerge. By school-age, delays become pronounced. Nonverbal skills remain on trajectory for mental age, whereas verbal deficits emerge and persist. Nonverbal learning and memory are strengths relative to verbal skills. Expressive language is delayed relative to comprehension. Aspects of language skills continue to develop throughout adolescence, although language skills remain compromised in adulthood. Deficits in attention/executive functions are present in childhood and become more pronounced with age. Characteristic features associated with DS (cheerful, social nature) are personality assets. Children are at a lower risk for psychopathology compared to other children with ID; families report lower levels of stress and a more positive outlook. In youth, externalizing behaviors may be problematic, whereas a shift toward internalizing behaviors emerges with maturity. Changes in emotional/behavioral functioning in adulthood are typically associated with neurodegeneration and individuals with DS are higher risk for dementia of the Alzheimer's type. Individuals with DS possess many unique strengths and weaknesses that should be appreciated as they develop across the lifespan. Awareness of this profile by professionals and caregivers can promote early detection and support cognitive and behavioral development.

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Comparison of conditioning impairments in children with Down syndrome, autistic spectrum disorders and mental age-matched controls

Abstract: These findings are discussed in terms of there implications for reward-based educational intervention programmes.

Cited by 11 publications

References 29 publications

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Down syndrome: Cognitive and behavioral functioning across the lifespan

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